Priapism is a disorder of non-willful, excessive penile erection recurrences affecting diverse populations. It particularly affects males with sickle cell disease (SCD), and as many as 40% of these individuals develop the disorder often in their young adult years. The disorder accounts for penile tissue damage and loss of normal erectile ability in time, along with devastating psychological consequences, and thus it should not be trivialized. Today, treatments remain lacking, and many men and boys endure delayed and ineffective therapies or manipulations of penile flaccidity associated with major side-effects. Recent efforts to better understand the science of the disorder offer hope to devise evidence-based therapies that are rational and effective. It is now understood that recurrent, ischemic priapism associated with SCD involves aberrations of the molecular mechanisms of normal penile erection associated with the premier nitric oxide signaling pathway. Androgens are well described to exert a direct regulatory influence on this pathway, and androgen deficiency is frequently observed to occur in SCD. Accordingly, it stands to reason that the androgen milieu contributes to the pathophysiology of priapism. The central hypothesis of this proposal is that a decline in androgen levels and actions contributes to the molecular derangements associated with priapism and, conversely, optimizing androgen status promotes regulatory molecular mechanisms that protect against priapism. The proposal specifies a translational project and combines preclinical studies testing the hypothesis (Specific Aim 1) and investigating the hypothalamic-pituitary-gonadal axis defect (Specific Aim 2) using a mouse model of SCD and clinical trial investigating the potential benefit of precise testosterone replacement for ameliorating priapism and improving psychological well- being (Specific Aim 3) in hypogonadal men with SCD. The proposal fits with goals of the funding agency pertaining to reproductive biology and testis function.